U.S. patent number 4,539,198 [Application Number 06/511,605] was granted by the patent office on 1985-09-03 for solid pharmaceutical formulations for slow, zero order release via controlled surface erosion: expanded range.
This patent grant is currently assigned to Rowell Laboratories, Inc.. Invention is credited to Vithal K. Patel, David R. Powell.
United States Patent |
4,539,198 |
Powell , et al. |
September 3, 1985 |
Solid pharmaceutical formulations for slow, zero order release via
controlled surface erosion: expanded range
Abstract
A new class of solid pharmaceutical formulations enables the
attainment of slow, zero order in vivo release of a wide range of
pharmaceutically active ingredients upon oral administration. A
broad range of release rates can be preselected by suitable
adjustments of tablet properties. The formulations are based upon
control of active ingredient release from the surface of the tablet
via a controlled surface erosion mechanism. These compositions
comprise: (a) an effective amount in the range of 10-90 wt. % of a
pharmacologically active compound having a water solubility
(20.degree. C.) of 1/5-1/1000 (w/w); (b) 1-40 wt. % of a compound
which is pharmaceutically acceptable in oral compositions and has a
water solubility (20.degree. C.) of 1/1-1/40 (w/w); (c) 2-20 wt. %
of a compound which is pharmaceutically acceptable in oral
compositions and has a water solubility (20.degree. C.) of 1/1-1/10
(w/w); (d) an amount in the range of 0.05-1.0 wt. % of a
disintegrating agent for pharmaceutical compositions, at which
amount the compound is ineffective as a disintegrating agent; (e)
0.1-2.0 wt. % of a surfactant which is pharmaceutically acceptable
in oral compositions; and, as necessary for tablet manufacturing
purposes; (f) 1-20 wt. % of a binder which is pharmaceutically
acceptable in oral compositions; or (g) 0.5-5.0 wt. % of a die wall
lubricant which is pharmaceutically acceptable in oral
compositions.
Inventors: |
Powell; David R. (Baudette,
MN), Patel; Vithal K. (Baudette, MN) |
Assignee: |
Rowell Laboratories, Inc.
(Baudette, MN)
|
Family
ID: |
24035636 |
Appl.
No.: |
06/511,605 |
Filed: |
July 7, 1983 |
Current U.S.
Class: |
424/464; 424/465;
514/161; 514/960 |
Current CPC
Class: |
A61K
9/2004 (20130101); A61K 31/60 (20130101); Y10S
514/96 (20130101) |
Current International
Class: |
A61K
31/60 (20060101); A61K 9/20 (20060101); A61K
009/22 (); A61K 009/32 (); A61K 009/36 (); A61K
031/60 () |
Field of
Search: |
;424/16,32,33,35,19-22,230 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
Other References
Porter et al., "The Permeability of Enteric Coatings and the
Dissolution Rates of Coated Tablets", Jun. 5, 1981, pp. 5-8. .
Remington's Pharmaceutical Sciences, 1970, pp. 1689-1691. .
Porter, "Tablet Coating," Jun. 1981, pp. 44, 46, 48, 50, 51, 86,
90, 92, 94. .
Luce, "Cellulose Acetate Phthalate: A Versatile Enteric Coating",
Jun. 1977. .
Rasmussen, "5-Aminosalicylic Acid in a Slow-Release Preparation:
Bioavailability, Plasma Level, and Excretion in Humans," 1982, pp.
1062-1070..
|
Primary Examiner: Rose; Shep K.
Attorney, Agent or Firm: Millen & White
Claims
What is claimed is:
1. A solid, orally administrable pharmaceutical tablet composition
having an enteric coating on its surface from which the active
ingredient has a slow, zero order release rate attained without
layers, beads or enteric materials and without relatively insoluble
polymers, waxes or gums when administered orally, said tablet being
compressed to a hardness of about 5-20 kg, and being either shaped
as a sphere, or else having a ratio of tablet thickness to tablet
diameter effective to permit tablet erosion and penetration control
sufficient for controlled surface erosion thereof, comprising an
essentially homogeneous, granulated mixture of:
(a) an effective amount in the range of about 10-90 wt. % of
5-aminosalicylic acid as a pharmacologically active compound having
a water solubility (20.degree. C.) of less than 1/500 to 1/1000
(w/w);
(b) about 1-40 wt. % of a surface controlling compound which is
pharmaceutically acceptable in oral compositions and has a water
solubility (20.degree. C.) of about 1/1-1/40 (w/w);
(c) about 2-20 wt. % of an erosion controlling compound which is
pharmaceutically acceptable in oral compositions and has a water
solubility of about 1/1-1/10 (w/w);
(d) an amount in the range of about 0.05-1.0 wt. %, of a surface
activator which is a disintegrating agent for pharmaceutical
compositions at which amount the compound is ineffective as a
disintegrating agent;
(e) about 0.1-2.0 wt. % of a surfactant which is pharmaceutically
acceptable in oral compositions, and, as necessary for tablet
manufacturing purposes;
(f) about 1-20 wt. % of a binder which is pharmaceutically
acceptable in oral compositions; or
(g) about 0.5-5.0 wt. % of a die wall lubricant which is
pharmaceutically acceptable in oral compositions;
the pharmacologically active ingredient thus having a slow, zero
order release rate when administered orally, and the
pharmacologically active compound not being a lithium compound, and
not being penny shaped or pancake shaped wherein the ratio of
thickness to diameter is too small for erosion and penetration
control.
2. A pharmaceutical composition of claim 1 consisting essentially
of all of ingredients (a)-(g).
3. A pharmaceutical composition of claim 1 wherein the amounts of
ingredients are as follows:
(a) 50-90 wt. %,
(b) 3-30 wt. %,
(c) 3-10 wt. %,
(d) 0.05-0.5 wt. %,
(e) 0.15-1.0 wt. %,
(f) 1-5 wt. %, and
(g) 1-4 wt. %.
4. A pharmaceutical composition of claim 1 having a spherical shape
or a ratio of tablet thickness to tablet diameter of about
0.5.+-.15%.
5. A pharmaceutical composition of claim 1 wherein all ingredients
have a particle size distribution in the fine (U.S.P.) or very fine
(U.S.P.) range.
6. A pharmaceutical composition of claim 1 further comprising, in
place of a corresponding amount of active ingredient (a), 1-80 wt.
% of an inert bulking excipient (h), pharmaceutically acceptable in
oral compositions and having a water solubility (20.degree. C.) of
less than 1/500 to 1/1000 (w/w).
7. A pharmaceutical composition of claim 1 wherein (b) is a
chloride, sulfate or phosphate of potassium, sodium or magnesium;
calcium citrate, phosphate, lactate, gluconate or succinate; a
mono- or di-saccharide or a correspondig polyhydric alcohol; a
natural amino acid; or an organic carboxylic or sulfonic acid; and
(c) is a mono- or di-saccharide or a corresponding polyhydric
alcohol; a natural amino acid; or an organic carboxylic or sulfonic
acid.
8. A pharmaceutical composition of claim 7 wherein (b) is an
inorganic salt and (c) is a mono- or di-saccharide or a
corresponding polyhydric alcohol.
9. A pharmaceutical composition of claim 8 wherein (b) is sodium
chloride or calcium phosphate monobasic; and (c) is mannitol,
lactose or sorbitol.
10. A pharmaceutical composition of claim 9 wherein
(b) is sodium chloride or calcium phosphate monobasic;
(c) is mannitol, lactose or sorbitol;
(d) is sodium starch glycolate;
(e) is sodium lauryl sulfate;
(f) is polyvinylpyrrolidone; and
(g) is calcium stearate.
11. A pharmaceutical composition of claim 5 prepared by first wet
granulating ingredients (a), (b) and (f) if present, to form a
homogeneous granulate; drying the resultant granulate; dry blending
the remaining ingredients with the dried granulate and compressing
the blend obtained into tablets of a hardness of 5-20 kg.
12. A method of orally administering an active ingredient (a) as
defined in claim 1 to a patient in need of treatment with (a), such
that (a) is released in vivo with a slow, zero order release rate,
comprising orally administering to such a patient a pharmaceutical
composition of claim 1.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
This application is related to U.S. Pat. Nos. 4,361,545 and
4,264,573, the former being a continuation-in-part of the latter.
The disclosures of these patents are incorporated by reference
herein in their entireties.
BACKGROUND OF THE INVENTION
The present invention relates to solid pharmaceutical formulations
whereby, upon oral administration, the active ingredients are
released with a selectable, usually slow, zero order rate.
Various techniques are known for formulating active ingredients to
selectively control the resultant release rate of the drug, e.g.,
via sustained release, slow release, fast release, etc.
It is important for any pharmaceutical formulation technique to
provide the capability of preselecting a desired release rate which
can be tailored to the unique characteristics of each drug. For
example, many formulations exist which permit selection of very
slow release rates, i.e., sustained release formulations. (See,
e.g., U.S. Pat. No. 3,641,236 based upon glycerol fatty acid esters
and U.S. Pat. No. 3,950,508 based upon alkyl celluloses and inert
powders such as talc, which, in combination with other ingredients,
produce a gradual disaggregation of the sustained release tablet.)
These can often cause toxicity and other side effects due to an
inordinately long presence of the drug in the body. Thus, methods
of preselecting somewhat faster release rates, i.e., slow release
rates--midway between fast and sustained rates--are needed.
Moreover, as Zaffaroni has suggested (Therapeutic Implications of
Controlled Drug Delivery, Future Trends in Therapeutics, Ed. F. C.
McMahon, Mount Kisco, N.Y., Futura Publishing, 1978, pp. 143-160),
an ideal drug delivery system would allow a constant amount of drug
to be absorbed per unit of time (zero-order kinetics). Thus, serum
concentrations would not fluctuate under steady-state conditions.
Weinberger et. al., The New England Journal of Medicine, Vol. 299,
No. 16, Oct. 19, 1978, pp. 852-857, have stated: "Modern technology
related to controlled oral delivery systems should be applied to
theophylline in an attempt to approximate zero-order absorption so
that the continuous stabilizing effect of this drug on the airways
can be maintained in the most effective, convenient and risk-free
manner." Similar sentiments have been echoed by many pharmaceutical
researchers in recognizing the preference for and importance of
zero order release rates for many drugs. See, e.g., U.S. Pat. No.
3,965,255. Nevertheless, zero order release has rarely been
achieved; there is no available technique by which a selected drug
can be systematically formulated to provide zero order release
kinetics in vitro or in vivo.
Furthermore, many formulations result in a bioavailability curve
having a high concentration peak at the beginning of release with a
subsequent tailing off at longer times. Such concentration peaks
are generally undesirable since they can lead to toxicity and/or
other adverse side effects. Additionally, they significantly limit
the freedom to increase the unit dosage of administration. Such an
increased dosage would correspondingly increase the peak
concentration. Under such circumstances, it is not possible to
decrease the frequency of administration by increasing the unit
dosage. This is a significant disadvantage in view of the well
established correlation between the likelihood that a patient will
fail to take doses of his medication and the required frequency of
administration. Zero order release would attentuate this adverse
effect by regulating the amount of active ingredient released in
vivo per unit of time.
As can be seen, in most instances, it is desirable to achieve a
relatively slow, zero order release rate of medication. This
precise rate should be easily selectable so that the resultant in
vivo absorption is desirably controlled and the bioavailability of
the drug is maximized.
SUMMARY OF THE INVENTION
Accordingly, it is an object of this invention to provide slow
release pharmaceutical formulations the amounts of whose
ingredients can be readily adjusted to provide in vivo, zero order
release for the active ingredient(s).
It is another object of this invention to provide such
pharmaceutical formulations by which the release rate and release
curve shape can be controlled in order to maximize in vivo
bioavailability of the active ingredient and/or minimize side
effects.
It is still another object of this invention to provide such
formulations which can be reproducibly manufactured by conventional
pharmaceutical methodology.
It is yet another object of this invention to provide such
formulations which are based on the principle of controlled surface
erosion and represent a significant modification and expansion of
the formulations of U.S. Pat. No. 4,361,545.
It is a further object of this invention to provide such
formulations comprising, as active ingredient, 5-aminosalicylic
acid (5-ASA).
Upon further study of the specification and appended claims,
further objects and advantages of this invention will become
apparent to those skilled in the art.
These objects have been attained by providing a solid, orally
administrable pharmaceutical composition from which the active
ingredient has a slow, zero order in vivo release rate when
administered orally, comprising:
(a) an effective amount in the range of 10-90 wt. % of a
pharmacologically active compound having a water solubility
(20.degree. C.) of 1/5-1/1000 (w/w) which, notably, includes the
new range of less than 1/500 to 1/1000;
(b) 1-40 wt. % of a compound which is pharmaceutically acceptable
in oral compositions and has a water solubility (20.degree. C.) of
1/1-1/40 (w/w);
(c) 2-20 wt. % of a compound which is pharmaceutically acceptable
in oral compositions and has a water solubility (20.degree. C.) of
1/1-1/10 (w/w);
(d) an amount in the range of 0.05-1.0 wt. % of a disintegrating
agent for pharmaceutical compositions, at which amount the compound
is ineffective as a disinte-grating agent;
(e) 0.1-2.0 wt. % of a surfactant which is pharmaceutically
acceptable in oral compositions; and, if necessary for tablet
manufacturing purposes,
(f) 1-20 wt. % of a binder which is pharmaceutically acceptable in
oral compositions; or
(g) 0.5-5.0 wt. % of a die wall lubricant which is pharmaceutically
acceptable in oral compositions,
the pharmacologically active compound thus having a slow, zero
order in vivo release rate when administered orally.
In another aspect, this invention provides a method of orally
administering an active ingredient to a patient in need of
treatment therewith, such that the drug is released in vivo with a
slow, zero order release rate, comprising orally administering a
pharmaceutical composition of this invention to such a patient.
In still another aspect, this invention provides a combination of
such a composition and an enteric coating whereby the onset of the
release of the drug is delayed until the composition reaches a
desired point in the gastrointestinal tract, e.g., when the active
agent is 5-ASA.
DETAILED DISCUSSION
In one aspect, this invention provides a significant expansion of
the applicability of the controlled surface erosion principles of
U.S. Pat. No. 4,361,545 in formulating pharmacologically active
compounds for zero order release. It has now been found that drugs
of a solubility in the low range of less than 1/500 to 1/1000 can
be formulated according to the details thoroughly described in U.S.
Pat. No. 4,361,545. This is a surprising and unexpected result
since, heretofore, it was thought that this formulation technique
was inapplicable to drugs having a solubility less than 1/500
(w/w).
Since all of the disclosures of U.S. Pat. No. 4,361,545 have been
incorporated by reference herein, and since, unless indicated
otherwise herein, all are fully applicable to this invention, the
following will summarize only a portion of these details, for
purposes of clarity. Examples relating to this new range are also
included.
Any drug of appropriate solubility can be formulated in accordance
with this invention. Especially suitable are those for which there
exists a specific reason for achieving zero order release and/or
other release curve shape effects, such as minimizing peak serum
levels. For example, such drugs include antibiotics, cardiovascular
agents, analgesics, antipyretics, antiinfectives, antacids,
gastrointestinal medications, steroids, CNS stimulants,
psychopharmacologic drugs, antineoplastic and immunosuppressive
drugs, antihistaminics, vitamins, essential minerals,
sympathomimetic and parasympathomimetic drugs, antitussives,
diuretics, sedatives, hypnotics, antiepileptics, decongestants,
antiasthmatics, etc. (Lithium formulations are the subject of the
claims of U.S. Pat. No. 4,264,573 mentioned above, and are excluded
from the claims of this application.)
In general, the amount of the active ingredient will be 10-90% by
weight of the tablet, or higher, e.g., 30-90%, typically 50-90%.
The drug should have a solubility in water (20.degree. C.) of about
1 weight part in 5 weight parts to 1 weight part in 1000 weight
parts, e.g., 1/5-1/500 or <1/500 to 1/1000, e.g., 1/10-1/500 w/w
or for the new regime of this invention, <1/500 to about 1/800,
1/560-1/1000, or about 1/800 w/w, etc. For many typical drugs, the
solubility is 1/50-1/300 w/w. In general, the half-life of the drug
will not be a factor since the formulation of this invention does
not produce sustained release but rather slow, controlled
release.
In addition to its role as a medicament, the active ingredient also
affects the precise release rate which is obtained, primarily by
contributing towards penetration control and cohesion because of
its solubility.
Ingredient (b) is termed the "surface controller" and functions
primarily as a surface uniformity control agent during dissolution
and erosion. The selection of a particular agent is not especially
critical as long as it is a pharmaceutically acceptable excipient
which is of the proper water solubility and compatible with oral
tablet manufacturing. Preferably, the agent should have a water
solubility (20.degree. C.) of about 1 weight part in 1 weight part
to 1 weight part in 40 weight parts; e.g., 1/1-1/20 w/w. Typically
the solubility is 1/2 to 1/30 w/w. It is usually employed in
amounts of 1-40% by weight of the final tablet, typically 3-30 wt.
%.
Suitable pharmaceutical excipients useful as surface controllers
include the generally preferred inorganic compounds such as the
chloride, sulfate and phosphate salts of potassium, sodium and
magnesium as well as the calcium citrate, phosphate, lactate,
gluconate and succinate salts. Suitable organic compounds for use
as the surface uniformity control agent include pharmaceutically
acceptable mono-saccharides and di-saccharides and the
corresponding polyhydroxy alcohols, for example, glucose, fructose,
lactose, dextrose, xylose, galactose, sucrose, maltose, sorbitol,
mannitol and xylitol. Other candidates include natural amino acids
and organic carboxylic or sulfonic acids.
Ingredient (c) is termed the "erosion controller" and serves as the
primary erosion rate controlling agent. Consequently, this
ingredient generally has a high water solubility, e.g., about 1
weight part in 1 weight part to 1 weight part in 10 weight parts,
e.g., 1/1-1/5 w/w, typically 1/1 to 1/5 w/w. Suitable such agents
also include pharmaceutically acceptable mono- and disaccharides
and the corresponding polyhydroxy, i.e., polyhydric alcohols,
natural amino acids, and organic carboxylic or sulfonic acids, all
of which is general should be suitable for dry mixing with the
active granulations or powders. For example, such agents include
sorbitol, mannitol, xylitol, lactose, glucose, xylose, galactose,
maltose, sucrose, dextrose, fructose, etc. The amount of this
ingredient is selected, inter alia, in accordance with the desired
rate of dissolution erosion and generally is in the range of 2-20%
based on the weight of the final tablet, e.g., 0.1-50, typically
3-10 wt. %, e.g., 5-10 wt. %.
Ingredient (d) of the inventive composition is termed the "surface
activator". Per se, these are fully conventional disintegration
agents employed in oral pharmaceutical tablets. However, they are
employed in amounts at which they are ineffectual as disintegrating
agents. Of course, since the formulations of this invention are to
provide slow release, effective amounts of these ingredients would
be incompatible. In fact, effective amounts would destroy the
controlled erosion phenomenon.
Instead of the conventional disintegrating effect, in the
heretofore never used low amounts, these disinte-grating agents
serve primarily to stabilize the controlled erosion phenomenon over
long term storage of the solid compositions. To some degree, they
also affect the finally achieved erosion rate, and correspondingly,
the release rate. This is probably accomplished through penetration
control effects. In other words, without these low amounts of the
surface activator, the zero order nature of the release rate of the
solid compositions could be accomplished but could not be stably
maintained over the long storage periods required in the
pharmaceutical field, e.g., 2-5 years, typically 3 years. As can be
seen, this is a necessary ingredient in the commercial
pharmaceutical tablets of this invention.
Such conventional disintegrating agents include starch and starch
derivatives, wood and cotton cellulose derivatives of the
microcrystalline or crosslinked types or other polymeric materials
etc. which are conventional disintegrants; see, e.g., Shangraw, et.
al., Pharmaceutical Technology, October, 1980, pp. 49-57 whose
disclosure is incorporated by reference herein. These surface
activators are employed in low, disintegrant ineffective but
surface activator effective concentrations of 0.05-1.0 wt. %,
typically 0.05-0.5 wt. %.
Ingredient (e) is a surface active agent which is also
pharmaceutically acceptable and fully conventional for use in oral
tablets. This ingredient provides wettability for any hydrophobic
components such as the stearates and also affects medium
penetration and surface erosion to some extent. Suitable such
conventional surfactants include sodium lauryl sulfate, magnesium
lauryl sulfate, dioctyl sodium sulfosuccinate, triethanolamine,
polyoxyethylene sorbitan, poloxalkol derivatives and quaternary
ammonium salts. In general, the surfactants have
hydrophile-lipophile balance ratios (HLB) of above 12. Surface
active agents are generally included in the composition in amounts
of 0.1-2% by weight of the final tablet, typically 0.15-1.0 wt.
%.
Under ideal circumstances, ingredients (a)-(e) would be sufficient
to achieve all purposes of this invention including zero order
release rates for the active ingredient in accordance with the
controlled erosion phenomenon. Such five component formulations,
however, will be rare since almost all active ingredients require
additional excipients to satisfy the demands of the tablet
manufacturing steps. Such tableting ingredients include the
familiar binders and dye wall lubricants, i.e., ingredients (f) and
(g) mentioned above.
Ingredient (f) of the pharmaceutical composition of this invention
is a fully conventional pharmaceutically acceptable binder for oral
tablets. These are normally employed to aid in the formation of
granules during the granulation step(s), to modify the compression
characteristics during the compression steps, or to aid during
other conventional tablet forming processes. As mentioned, the
compositions of this invention achieve slow release at zero order
using only the relatively soluble ingredients discussed above.
Binders, e.g., gums, waxes, relatively insoluble polymers, etc.,
previously needed to achieve such slow release rates in
conventional sustained release compositions and many other slow
release compositions, are obviated. These ingredients are employed
only where desirable, or necessary for tableting purposes, per
se.
Suitable such fully conventional pharmaceutical binders include
povidone (polyvinylpyrrolidone), polyvinylalcohol,
polyethyleneglycol, sucrose, lactose, gelatin, starch paste,
acacia, tragacanth, etc.
In general, when present, the binders are included in the inventive
pharmaceutical composition in amounts of 1-20% by weight, of the
final tablet, typically 1-5 wt. %. When binders are absent, the
composition of this invention will be inherently compressable
and/or granulatable, e.g., by the slugging technique or by the
addition of a subsequently evaporatable, activating solvent such as
water, alcohol, acetone, etc. In addition to the primary binding
effect of this ingredient, wettability control and penetration
control will sometimes be affected to some degree by its inclusion,
depending, of course, on the specific characteristics of the
particular binder employed.
Ingredient (g) is a fully conventional, pharmaceutically acceptable
die wall lubricant for inclusion in oral tablets. This ingredient
is required in order to facilitate the ejection of the tablet from
the die after the compression step by lubrication of the tableting
tool. Suitable such conventional die wall lubricants include the
stearate salts such as calcium, magnesium, and zinc, as well as
stearic acid, mineral oil, vegetable oil derivatives, polyethylene
glycols, talc, etc. In general, 0.5-5% by weight of the final
tablet of this ingredient is included, i.e., amounts in which these
ingredients function as die wall lubricants, typically 1-4 wt.
%.
Ingredients (e) and (g) may also be added to the composition in
conventionally combined form. Such combinations are commercially
available and are provided as a homogeneous mixture of the two
ingredients prepared by spray drying or other techniques. Such
commercially available combined lubricants and surface active
systems include Stear-o-wet C and Stear-o-wet M.
Very often, an active ingredient is dosed in high concentrations.
Typical such high dosage drugs include lithium, theophylline,
quinidine sulfate, etc. Such drugs are dispensed in unit dosages
from 50-500 mg, for example. For other high dosage drugs, unit
dosages are as high as 1000 or 1500 mg. Such dosages are quite
readily compatible with the pharmaceutical composition of this
invention as defined above. However, it is often desired to
formulate drugs in dosage ranges of less than 50 mg, e.g., 1-<50
mg per tablet yet still retain conventionally sized tablets. In
such situations, ingredient (h) can be incorporated into the tablet
replacing a corresponding amount of the active ingredient per se.
In this way, slow release base formulations for the more potent
type of drugs can be prepared at low dosages.
Since excipients (h) are used to replace active ingredient (a),
they should have the same solubility properties, e.g., water
solubilities (20.degree. C.) of about 1 weight part in 5 weight
parts to 1 weight part in 1000 weight parts, e.g., 1/5-1/500 or
<1/500 to 1/1000, e.g., 1/10-1/500 w/w or for the new regime of
this invention, <1/500 to about 1/800, 1/560-1/1000, or about
1/800 w/w, etc. For many typical drugs, the solubility is
1/50-1/300 w/w. The amount of this innocuous bulking excipient,
i.e., inert filler, is to be chosen depending upon the desired
dosage of the active ingredient as well as the other factors
discussed above with respect to the active ingredient per se.
Generally, the amount of ingredient (h) is 1-80% by weight of the
finally produced tablet, depending on the desired tablet size.
Such innocuous bulking excipients (fillers) are fully conventional
and include the pharmaceutically acceptable excipients for oral
tablets such as inorganic salts, both mineral and mineral organic,
carbohydrates, proteins, emulsifiable fats and the like. Specific
examples include calcium salts, such as the lactate, gluconate,
glycerylphosphate, citrate, phosphate monobasic and dibasic,
succinate, sulfate and tartrate, as well as the same salts of
aluminum and magnesium. Typical such carbohydrates include the
conventional mono- and disaccharides as well as the corresponding
polyhydric alcohols.
Manufacture of the formulations is in accordance with the details
given in the mentioned U.S. Pat. Nos. 4,361,545 and 4,264,573. As
mentioned therein, coatings can be used on the formulations of this
invention to tailor the onset of drug release for a given purpose,
e.g., to delay it until the formulation reaches a desired location
of the gastrointestinal tract, e.g., enteric coatings which enable
bypassing of the stomach and initiation of release in the small
intestine. The manufacture, design and compositions of such
coatings are fully conventional, e.g., as disclosed in Porter et
al, "The Permeability of Enteric Coatings and the Dissolution Rates
of Coated Tablets", J. Pharm. Pharmacol. 1982: 34:5-8; Remington's
Pharmaceutical Sciences, Ed. Osol et al, e.g., 1689-1691, 14th Ed.,
Mack Publishing Co. (1970); Porter, "Tablet Coating", Drug &
Cosmetic Industry, June 1981, 44-51, 86-94; Luce, "Cellulose
Acetate Phthalate: A Versatile Enteric Coating", Pharmaceutical
Technology, June 1977; as well as, data sheets provided with many
commercial products such as, Eudragit-L, Eudragit-L (Aqueous
Dispersion), Eudragit-S, etc. (all by Rohm and Haas, Germany);
PVAP, OPADRY, etc. (all by Colorcon, Inc., West Point, Pa.), etc.,
all of whose disclosures are incorporated by reference herein. As
mentioned, these coatings are not expected to achieve the desired
release rate per se--controlled surface erosion accomplishes that.
They merely serve as time delays for onset of the release mechanism
of this invention.
Drugs in the new solubility range defined in this invention include
5-aminosalicyclic acid (5-ASA) which is useful, e.g., to treat
ulcerative colitis and Crohn's disease. (See, e.g., Rasmussen et
al, Gastroentology 1982:83: 1062-70, whose disclosure is
incorporated by reference herein). It is particularly desirable to
employ an enteric coating in conjunction with 5-ASA to delay the
onset of release of the drug to the small intestine and/or large
intestine.* Other drugs in the new solubility range include
oxypertine, allobarbitone, allylbarbituric acid, 4-aminosalicyclic
acid, amisometradine, carbimazole, cyclobarbitone, salicylic acid,
saliclamide, carphenazine maleate, cocaine, dextrothyroxine sodium,
metharbital, etc.
Without further elaboration, it is believed that one skilled in the
art can, using the preceding description, utilize the present
invention to its fullest extent. The following preferred specific
embodiments are, therefore, to be construed as merely illustrative,
and not limitative of the remainder of the disclosure in any way
whatsoever. In the following examples, all temperatures are set
forth uncorrected in degrees Celsius; unless otherwise indicated,
all parts and percentages are by weight.
EXAMPLE 1
5-ASA Tablets
______________________________________ Composition % W/W Typical
______________________________________ 5-Aminosalicyclic Acid
(5-ASA) 73.3 Sodium Chloride 11.7 Povidone** 4.4 Alcohol SDA-3A,
q.s. -- Lactose 8.8 Calcium Stearate/Sodium Lauryl Sulfate* 1.76
Sodium Starch Glycolate 0.29 ______________________________________
*as defined in Example 2; **polyvinylpyrrolidone
The sodium chloride is milled through a Whistler mill using a small
slotted screen. The 5-ASA is combined with the sodium chloride and
mixed for 5 minutes in a ribbon blender. The powder blend is milled
through a Fitz mill at high speed (1B band) and returned to the
ribbon blender. Povidone/alcohol solution is added to the powder
blend while the mixer is running to form a wet mass. The wet mass
is passed through a Fitz mill (1/2 inch, perforated band) with
hammers forward at high speed. The wet granulation is trayed and
dried for 16 hours at 55.degree. C. The dried mixture is sized
through a Fitz mill (2A band) with knives forward at medium speed.
The resultant blend is placed in a ribbon blender. Lactose, calcium
stearate/sodium lauryl sulfate and sodium starch glycolate is
passed through a 40 mesh screen. The screened powders are added to
the ribbon blender and mixed for 5 minutes. On a conventional
tablet press, the finished granulation is compressed into 3/8"
tablets using standard concave tooling. The tablets meet the target
weight requirements, are about 0.175 in. thick, have a hardness of
8-15 kilopounds and a friability of NMT 0.4%.
ENTERIC COATING
100 kg of compressed tablets is placed into an Accela-Cota pan and
warmed to about 40.degree. C. exhaust temperature. 5 kg of Opadry
Enteric (Colorcon, Inc.) is dispersed in an alcohol (SDA-3A)-water
mixture (composition of alcohol/water is 25.5 kg and 2.8 kg
respectively). This solution is spray coated on tablets using an
air-atomization system as follows: 2 spray guns at 35 psi each set
to deliver about 60 g/minute, maintaining an exhaust temperature of
35'-45.degree. C. The coated tablets are dried in the Accela-Cota
pan for 1 hour at 35.degree.-45.degree. C. The tablets are polished
in the pan using 1 gram of powdered Carnauba Wax.
EXAMPLE A PRELIMINARY TESTING
Pilot Batch Formulation and Optimization:
Batch Size: 5000 tablets
Base Granulation:
______________________________________ Per Tablet (mg) % w/w*
______________________________________ 5-Aminosalicylic Acid 250
72.00 Sodium Chloride 40 11.50 .sup.+ Plasdone USA 20 5.80 Alcohol
SDA-3A (granulating -- solvent, removed by drying)
______________________________________ Manufacturing: Wet milling
and dry milling of granulation using Homoloid mill. .sup.+ :
polyvinylpyrrolidone by GAF *: of final tablet composition
SIZED GRANULATION
Flow: Very good
Tapped Bulk Density: 0.5 gram/ml
Chromatographic Purity Test:
Objective: To detect any interaction between 5-Aminosalicylic Acid
and Alcohol SDA-3A (methyl or ethyl ester of 5-ASA).
Rf
5-ASA 0.26
No other foreign spot on the TLC plate.
EXAMPLE 2
Using the base granulation of 5-ASA from Example A and the
procedure of Example 1, controlled surface erosion ingredients were
added. The formulations are shown below.
______________________________________ Func- Ingredient tion weight
(mg) Composition Class 1 2 3 % w/w
______________________________________ 5-Aminosalicylic a 250 250
250 72.20 Acid Sodium Chloride b 40 40 40 11.50 Plasdone USP f 20
20 20 5.80 *Stear-o-wet-C e/g 6 6 6 1.70 Sodium Starch d 0.5 0.5
0.5 0.14 glycolate Lactose Po. c 40 -- -- 11.50 Mannitol c -- 40 --
11.50 Sorbitol c -- -- 40 11.50 Theor. Tablet 346.5 346.5 346.5
Weight ______________________________________ *6 mg of Stearo-wet-C
consists of 0.36 mg of sodium lauryl sulfate and 5.64 mg of calcium
stearate. Batch Size: 500 Tablets Compressed on `E` machine using
3/8" standard concave tooling, upper and lower plain.
Tablet Formulation Evaluation:
______________________________________ Test 1 2 3
______________________________________ Compressibility Excellent
Excellent Excellent Flow Very good Very good Very good Avg. Tablet
Wt. 348 mg 342 mg 344 mg Thickness 0.177" 0.177" 0.178" Hardness 14
KP 12 KP 11 KP Friability 0.09% 0.12% 0.14%
______________________________________
DISSOLUTION DATA
Dissolution Procedure:
Dissolution Apparatus: USP Method II, (Paddle)
Paddle Rotation Speed: 100 rpm
Dissolution Medium: 900 ml, pH 7.0, phosphate buffer in deaerated
water RODI.
______________________________________ *Cumulative % Dissolved
Time, of Label Claim Minutes 1 2 3
______________________________________ 15 8.6 8.2 9.1 30 16.7 15.7
17.3 60 34.1 33.7 34.3 120 59.8 58.4 58.3 180 80.8 84.2 86.6
Statistical Analysis for fit to zero order release T.sub.50%,
Minutes 103.8 102.8 100.2 Dissolution Rate 1.0945 1.1436 1.154
mg/min. Correlation 0.9998 0.9992 1.004 Coefficient (R) excellent
linearity ______________________________________ *Avg. of 6
tablets, samples were pooled.
EXAMPLE 3
The formulation used in Example 2 was optimized as follows using
the same procedure:
______________________________________ Function Per Tab- Ingredient
Class let (mg) % w/w ______________________________________
5-Aminosalicylic Acid a 250 72.15 Sodium chloride b 40 11.54
Plasdone f 20 5.77 Lactose powder c 30 8.65 Stear-o-wet C e/g 6
1.73 Sodium starch glycolate d 0.5 0.14 Theor. Tablet Weight 346.5
______________________________________
Batch Size: 4000 Tablets
COMPRESSION
Using rotary tablet press and 3/8" standard concave tooling, upper
and lower plain, excellent compressibility.
TABLETS
Hardness: 13.2 KP
Friability: 0.08%
Wt. Variation: Passes (.+-.1% of avg. wt.)
Average Tablet Wt.=347.6 mg
DISSOLUTION DATA
5-ASA SR Tablet 250 mg
Dissolution Profile:
Dissolution Procedure: As in Example 2.
______________________________________ Tablet Cumulative %
Dissolved of Label Claim Number 15 min. 30 min. 60 min. 120 min.
180 min. ______________________________________ 1 9.4 16.0 36.2
78.5 105.8 2 7.9 16.0 30.3 62.6 99.1 3 8.0 16.7 31.2 69.4 101.9 4
8.9 17.2 31.40 68.6 104.0 5 8.6 17.2 33.30 71.90 102.8 6 9.2 17.4
31.40 62.70 100.8 Avg. 8.66 16.75 32.3 68.95 102.4 % RSD 7.10 3.73
6.65 8.69 2.3 ______________________________________
STATISTICAL ANALYSIS FOR FIT TO ZERO-ORDER RELEASE
T.sub.50% =86.3 minutes
Dissolution Rate: 1.43 mg/minute
Correlation Coefficient (R)=0.9998 (excellent linearity)
EXAMPLE 4
200 tablets were prepared in a continuation of the work performed
in Examples 2 and 3 using the same procedures.
______________________________________ Function Per Tab- %
Ingredient Class let (mg) w/w
______________________________________ 5-Aminosalicylic Acid a 250
73.31 Sodium chloride b 40 11.73 Plasdone f 15 4.40 Lactose Po.
(200 mesh) c 30 8.80 Stear-o-wet C e/g 6 1.76 Sodium starch
glycolate d 0 0.0 Alcohol SDA-3A as a granulating solvent Target
weight = 341 ______________________________________
FINISHED GRANULATION
Flow: Very good
Compressibility: Very good
Tablets (Uncoated): Compressed on rotary tablet press using 3/8"
standard concave tooling both upper and lower plain.
Average Tablet Wt.: 345 mg
Hardness: 10 KP (8-11 KP)
Thickness: 0.176"
Friability: 0.10%
Dissolution Data:
Dissolution Test Procedure: USP dissolution apparatus II (paddle
method), 100 rpm, pH 7.0, phosphate buffer in deaerated RODI water,
900 ml.
______________________________________ Cumulative % Dissolved of
Label Claim Tablet Time, Minutes Number 15 30 60 120 180 240
______________________________________ 1 6.6 12.1 23.40 43.9 63.2
80.5 2 7.7 13.2 23.60 45.0 63.9 78.2 3 7.3 13.8 28.3 57.8 78.0 91.6
4 6.6 12.2 25.1 49.0 70.7 87.0 5 7.3 13.4 25.5 48.8 68.2 85.2 6 7.3
12.9 24.3 53.0 71.7 85.4 Avg. 7.1 12.9 25.0 49.6 69.3 84.7 % RSD
6.2 5.0 7.1 10.4 7.9 5.6 ______________________________________
STATISTICAL ANALYSIS FOR FIT TO ZERO ORDER RELEASE
T.sub.50% =131.9 minutes
Dissolution Rate: 0.88 mg/minute (0.35%/min. 100 rpm paddle)
Correlation Coefficient (R)=0.998 (excellent linearity) This
example demonstrates that ingredient (d) is not absolutely
necessary for achievement of zero order release by controlled
surface erosion. It is, however, necessary for stability
requirements.
EXAMPLE 5
1000 tablets of the following composition were prepared using the
procedures of Example 1.
______________________________________ Function Per Tab- %
Ingredient Class let (mg) w/w
______________________________________ 5-Aminosalicylic Acid a 250
73.3 Sodium chloride b 40 11.7 Plasdone f 15 4.4 Lactose Powder
(200 mesh) c 30 8.8 Stear-o-wet C e/g 6 1.76 Sodium starch
glycolate d 1.0 0.29 Alcohol SDA-3A as a granulating solvent Total
weight = 342 ______________________________________
FINISHED GRANULATION
Flow: Very good
Compressibility: Very good
Tablets: Compressed on rotary tablet press using 3/8" standard
concave tooling, both upper and lower plain.
Hardness: 10 KP
Thickness: 0.176"
Friability: 0.08%
Average Tablet Weight: 344 mg.
Dissolution Data:
Dissolution Test Procedure: Same as in Example 2.
______________________________________ Cumulative % Dissolved of
Label Claim Tablet Time, Minutes Number 15 30 60 120 180
______________________________________ 1 8.7 14.8 40.5 65.4 86.0 2
14.6 29.6 48.1 73.1 95.0 3 8.8 17.7 35.7 64.4 90.0 4 9.6 19.0 38.0
67.8 94.0 5 10.1 21.0 45.9 74.9 98.0 6 9.7 20.0 48.1 77.1 98.9 Avg.
10.3 20.4 42.7 70.5 93.7 % RSD 21.4 24.6 12.6 7.5 5.2
______________________________________
STATISTICAL ANALYSIS FOR FIT TO ZERO ORDER RELEASE
T.sub.50% =85.9 minutes
Dissolution Rate=1.257 mg/minute (0.5%/min. 100 RPM paddle)
Correlation Coefficient (R)=0.995 (excellent linearity)
The preceding examples can be repeated with similar success by
substituting the generically or specifically described reactants
and/or operating conditions of this invention for those used in the
preceding examples.
From the foregoing description, one skilled in the art can easily
ascertain the essential characteristics of this invention, and
without departing from the spirit and scope thereof, can make
various changes and modifications of the invention to adapt it to
various usages and conditions.
* * * * *